Asymmetric synthesis of the dibenzocyclooctadiene lignans interiotherin A and gomisin R

Article abstract of DOI:10.1021/ol050476t

(Chemical Equation Presented) Asymmetric total syntheses of the dibenzocyclooctadiene lignans interiotherin A and angeloylgomisin R are reported. The syntheses were based on an atropdiastereoselective, copper-promoted biaryl coupling reaction, a diastereo

Full text of DOI:10.1021/ol050476t

ORGANIC
LETTERS
2005
Vol. 7, No. 9
1849-1852
Asymmetric Synthesis of the
Dibenzocyclooctadiene Lignans
Interiotherin A and Gomisin R†
Robert S. Coleman* and Srinivas Reddy Gurrala
Department of Chemistry, The Ohio State UniVersity, 100 West 18th AVenue,
Columbus, Ohio 43210
coleman@chemistry.ohio-state.edu
Received March 4, 2005
ABSTRACT
Asymmetric total syntheses of the dibenzocyclooctadiene lignans interiotherin A and angeloylgomisin R are reported. The syntheses were
based on an atropdiastereoselective, copper-promoted biaryl coupling reaction, a diastereoselective hydroboration/Suzuki
−Miyaura coupling
reaction sequence, and an asymmetric boron-mediated tiglylation of an aryl aldehyde precursor.
Lignans are plant-derived natural products formed by dimer-
ization of the nine-carbon skeleton of cinnamic acid. Dif-
ferent families of lignans include the aryltetrahydronaphtha-
lenes, typified by podophyllotoxin, the arylnaphthalenes, and
the diverse family of dibenzocyclooctadienes.1 A wide variety
of dibenzocyclooctadiene lignans are produced by the
Schisandraceae family of plants, including schisandrin C,
gomisins, and kadsurin, many of which are biologically
active.2 Although a variety of synthetic efforts toward these
natural products have been reported over the years,3 there
has been a resurgence of interest in this area. Efforts by
Molander and co-workers have been notable.4
A recent report described the isolation of interiotherins A
(1) and B from the stems of Kadsura interior,5 a vine of the
Schisandraceae family native to southern China. This group
subsequently reported the isolation of the more highly
modified lignans interiotherins C and D.6 The interiotherins
inhibit the replication of HIV at µg/mL levels. Interiotherin
A is closely related to angeloylgomisin R (2).7
As part of a research program focused on the chemistry
and biology of dibenzocyclooctadiene lignans, we report the
first asymmetric total syntheses of interiotherin A and
angeloylgomisin R. The basis of our synthetic approach to
these natural products (Scheme 1) was fourfold, where each
bond-forming event introduces a key stereogenic element of
the target molecules: (1) installation of the C6 ester side-
chains of the natural products by a Mitsunobu reaction,
(3) (a) Takeya, T.; Yamaki, S.; Itoh, T.; Hosogai, H.; Tobinaga, S. Chem.
Pharm. Bull. 1996, 44, 909. (b) Tanaka, M.; Mukaiyama, C.; Mitsuhashi,
H.; Maruno, M.; Wakamatsu, T. J. Org. Chem. 1995, 60, 4339. (c) Takeya,
T.; Ohguchi, A.; Tobinaga, S. Chem. Pharm. Bull. 1994, 42, 438. (d) Takeya,
T.; Ohguchi, A.; Ara, Y.; Tobinaga, S. Chem. Pharm. Bull. 1994, 42, 430.
(e) Takeya, T.; Ohguchi, A.; Ikeya, T.; Tobinaga, S. Chem. Pharm. Bull.
1994, 42, 677. (f) Warshawsky, A. M.; Meyers, A. I. J. Am. Chem. Soc.
1990, 112, 8090. (g) Ishiguro, T.; Mizuguchi, H.; Tomioka, K.; Koga, K.
Chem. Pharm. Bull. 1985, 33, 609. (h) Tomioka, K.; Mizuguchi, H.; Koga,
K. Tetrahedron Lett. 1979, 16, 1409. (i) Kende, A. S.; Liebeskind, L. S. J.
Am. Chem. Soc. 1976, 98, 267.
(4) Molander, G. A.; George, K. M.; Monovich, L. G. J. Org. Chem.
2003, 68, 9533. Monovich, L. G.; Hue´rou, Y. L.; Ro¨nn, M.; Molander, G.
A. J. Am. Chem. Soc. 2000, 122, 52.
(5) Chen, D.-F.; Zhang, S.-X.; Chen, K.; Zhou, B.-N.; Wang, P.;
Consentino, L. M.; Lee, K.-H. J. Nat. Prod. 1996, 59, 1066.
† Dedicated to the memory of Professor Herbert C. Brown, whose
contributions to science made this and countless other syntheses feasible.
(1) Ayres, D. C.; Loike, J. D. Lignans. Chemical, Biological and Clinical
Properties; Cambridge University Press: Cambridge, UK, 1990.
(2) Charlton, J. L. J. Nat. Prod. 1998, 61, 1447.
(6) Chen, D.-F.; Zhang, S.-X.; Kozuka, M.; Sun, Q.-Z.; Feng, J.; Wang,
Q.; Mukainaka, T.; Nobukuni, Y.; Tokuda, H.; Nishino, H.; Wang, H.-K.;
Morris-Natschke, S. L.; Lee, K.-H. J. Nat. Prod. 2002, 65, 1242.
(7) Tan, R.; Li, L. N.; Fang, Q. Planta Med. 1984, 50, 414.
10.1021/ol050476t CCC: $30.25
© 2005 American Chemical Society
Published on Web 03/29/2005

Scheme 1
Scheme 3
Aldehyde 8 (Scheme 3) was prepared following our route
used in the synthesis of eupomatilones 4 and 6.11 Borane 9
was prepared from (E)-1-bromo-2-methyl-2-butene (tiglyl
bromide) via the intermediate Grignard reagent by reaction
with (-)-B-chlorodiisopinocampheylborane [(-)-DIP-Cl].12
The Grignard reagent equilibrates,13 so both (Z)- and (E)-
isomers of the methylcrotylborane 9 were formed and a 4:3
mixture of separable syn and anti adducts 13 and 14,14
respectively, was produced in 97% combined yield. The anti
isomer was produced in >95:5 enantiomeric ratio and
protected as the tert-butyldimethylsilyl ether to afford 15.
Hydroboration of the alkene of 15 with 9-BBN afforded
the intermediate trialkylborane 16 (Scheme 4), which was
concurrently setting the stereochemistry at C6; (2) intramo-
lecular, atropdiastereoselective Lipshutz biarylcuprate coup-
ling between C15 and C16 of 4 to afford the parent di-
benzocyclooctadiene ring system in 3; (3) diastereoselective
hydroboration of the C8-C9 alkene of 7 followed by in situ
Suzuki-Miyaura coupling of the resulting C9 alkylborane
5 with aryl bromide 6; (4) asymmetric crotylation of aldehyde
8 with the Brown borane 9, prepared from tiglyl bromide,
to afford 7.
Scheme 4
Selective alkylation8 of the less acidic phenol of 2,3-
dihydroxybenzaldehyde with benzyl bromide provided start-
ing aldehyde 10 (Scheme 2). Bromination of 10 under
Scheme 2
used directly in a subsequent Suzuki-Miyaura coupling
reaction15 with aryl bromide 12. The product of this reaction,
(11) Coleman, R. S.; Gurrala, S. R. Org. Lett. 2004, 6, 4025.
(12) Brown, H. C.; Jadhav, P. J. Am. Chem. Soc. 1983, 105, 2092. Brown,
H. C.; Bhat, K. S. J. Am. Chem. Soc. 1986, 108, 293. Brown, H. C.; Bhat,
K. S. J. Am. Chem. Soc. 1986, 108, 5919. Racherla, U. S.; Brown, H. C. J.
Org. Chem. 1991, 56, 401.
(13) Schlosser, M. Angew. Chem., Int. Ed. Engl. 1974, 13, 701. Schlosser,
M.; Hartman, J.; David, V. HelV. Chim. Acta 1974, 57, 1567. Schlosser,
M.; Hartman, J. J. Am. Chem. Soc. 1976, 98, 4674. Fuzita, K.; Schlosser,
M. HelV. Chim. Acta 1982, 65, 1258.
(14) Enantiomeric ratio of the diastereomerically pure anti adduct 14
was measured by chiral HPLC (OD column).
standard conditions provided aryl bromide 119 (95%). Dakin
oxidation10 afforded the corresponding catechol, which was
transformed into the methylenedioxy system 12 in 80% yield
for the two-step sequence.
(8) (a) Parker, K. A.; Georges, A. T. Org. Lett. 2000, 2, 497. (b) Nicolaou,
K. C.; Sasmal, P. K.; Xu, H.; Namoto, K.; Ritzen, A. Angew. Chem., Int.
Ed. 2003, 42, 4225.
(9) Nicolaou, K. C.; Sasmal, P. K.; Xu, H. J. Am. Chem. Soc. 2004,
126, 5493.
(10) Larsson, S.; Miksche, G. E. Acta Chem. Scand. B 1972, 26, 2031.
(15) (a) Miyaura, N.; Suzuki, A. Chem. ReV. 1995, 95, 2457. (b) Chemler,
S. R.; Trauner, D.; Danishefsky, S. J. Angew. Chem. Int. Ed. 2001, 40,
4544.
1850
Org. Lett., Vol. 7, No. 9, 2005

1,4-diarylbutane 17 was produced in 77% isolated yield for
the two-step protocol as a 97:3 diastereomeric ratio of
isomers. Diastereofacial selectivity can be explained using
a standard A1,3 strain argument, which has precedent in our
work11 and in the work of others.16 At the stage of 17, the
key issue remaining is formation of the biaryl bond and the
accompanying question of atropdiastereoselection.
Installation of the aryl bromide for biaryl coupling was
accomplished in 84% overall yield for the three-step reaction
sequence: (1) hydrogenolysis of the benzyl ether of 17
(EtOAc, 6 h, 25 °C, 98%) afforded phenol 18; (2) selective
bromination ortho to the phenolic hydroxyl group of 18 (15
°C, 12 h, 90%) provided bromide 19; (3) alkylation of the
phenolic hydroxyl group (K2CO3, acetone, 95%) afforded
methyl ether 20 (Scheme 5). It is well established that
bromination can be selectively achieved ortho to a phenolic
hydroxyl group.17
lithiated system, which was reacted directly with cuprous
cyanide at -40 °C to form an intermediate cyclic, higher-
order biarylcuprate. Oxidation occurred smoothly using
oxygen, as originally described, or more effectively using
1,3-dinitrobenzene,20 and dibenzocyclooctadiene 21 was
isolated in 69% yield as the sole diastereomer present.
Removal of the silyl ether of 21 (THF, 55 °C, 12 h) afforded
the corresponding alcohol 22.
Assignment of absolute configuration about the biaryl axis
of 21 was obtained by correlation of key 1H NMR chemical
shifts with those of the related system 23,21 whose relative
configuration was determined by single-crystal X-ray crystal-
lographic analysis (Figure 1). In the structure of 23, the Paxial
Scheme 5
Figure 1. X-ray Structure of dibenzocyclooctadiene (P)-23.
configuration about the stereogenic biaryl bond correlates
with the 6S,7S,8S configuration at the stereogenic centers
of the four-carbon bridge.
These C6, C7, and C8 stereogenic centers of precursor
20 therefore control the sense of axial chirality during the
formation of the biaryl bond, such that this stereogenic axis
is introduced with a high degree of selectivity. We observed
that oxidative cuprate coupling of the corresponding 1,2-
syn/2,3-anti diastereomer of 1,4-diarylbutane 20 afforded a
3:2 mixture of configurationally undefined stereoisomers.
Alcohol 22 underwent a Mitsunobu reaction/inversion with
benzoic acid (Scheme 6) to afford interiotherin A (1). In a
similar manner, reaction of alcohol 22 with angelic acid
under Mitsunobu reaction conditions afforded angeloylgo-
Implementation of the Lipshutz methodology for biaryl
coupling,18 which involves oxidation of a mixed biarylcuprate
species to effect formation the carbon-carbon biaryl bond,
proved ideal in this system. This reaction is insensitive to
steric or electronic features of aromatic systems, and we have
successfully used it with other sterically crowded, electron-
rich aromatic systems.11,19
In the present case (Scheme 5), halogen-lithium exchange
of 20 with tert-butyllithium afforded an intermediate bis-
1
misin R (2). The H and 13C NMR data for synthetic 1 and
2 were identical with those reported for the naturally
occurring compounds.
As it turned out, our concerns about the regioselectivity
of bromination (Scheme 5) were unwarranted. Suzuki-
Miyaura coupling of borane 16 with the methoxy-substituted
aryl bromide 2422 occurred smoothly to afford 1,4-diarylbu-
(16) (a) Hoffmann, R. W.; Dahmann, G.; Andersen, M. W. Synthesis
1984, 629. (b) Coutts, L. D.; Cywin, C. L.; Kallmerten, J. Synlett 1993,
696. (c) Bernsmann, H.; Fro¨lich, R.; Metz, P. Tetrahedron Lett. 2000, 41,
4347. (d) Araki, K.; Suenaga, K.; Sengoku, T.; Uemura, D. Tetrahedron
2002, 58, 1983. (e) Herb, C.; Maier, M. E. J. Org. Chem. 2003, 68, 8129.
(17) (a) Fujisaki, S.; Eguchi, H.; Omura, A.; Okamoto, A.; Nishida, A.
Bull. Chem. Soc. Jpn. 1993, 66, 1576. (b) Pearson, D. E.; Wysong, R. D.;
Breder, C. V. J. Org. Chem. 1967, 32, 2358.
(18) (a) Lipshutz, B. H.; Siegmann, K.; Garcia, E. J. Am. Chem. Soc.
1991, 113, 8161. (b) Lipshutz, B. H.; Siegmann, K.; Garcia, E.; Kayser, F.
J. Am. Chem. Soc. 1993, 115, 9276. (c) Lipshutz, B. H.; Kayser, F.; Maullin,
N. Tetrahedron Lett. 1994, 35, 815. (d) Lipshutz, B. H.; Liu, Z.-P.; Kayser,
F. Tetrahedron Lett. 1994, 35, 5567. (e) Lipshutz, B. H.; Kayser, F.; Liu,
Z.-P. Angew. Chem., Int. Ed. Engl. 1994, 33, 1842.
(20) (a) Spring, D. R.; Krishnan, S.; Schreiber, S. L. J. Am. Chem. Soc.
2000, 122, 5656. (b) Ref 18b.
(21) Characteristic chemical shifts for (P)-23: C4-H/C10-H δ 7.02/
6.50; C6-H δ 4.42; C7-CH3/C8-CH3 δ 1.03/0.66. For (M)-23: C4-H/
C10-H δ 6.47/6.36; C6-H δ 4.73; C7-CH3/C8-CH3 δ 1.17/0.97. For
compound 21: C4-H/C10-H δ 6.87/6.43; C6-H δ 4.37; C7-CH3/C8-
CH3 δ 0.98/0.65.
(19) Coleman, R. S.; Grant, E. B. J. Am. Chem. Soc. 1994, 116, 8795.
Coleman, R. S.; Grant, E. B. J. Am. Chem. Soc. 1995, 117, 10889.
Org. Lett., Vol. 7, No. 9, 2005
1851

Scheme 6
Scheme 7
a potentially general route to the dibenzocyclooctadiene
family of lignans. While the asymmetric crotylation reaction
(8 + 9) occurs with little diastereoselection as a result of
the inability to form crotylborane in geometrically pure form,
this problem is under active investigation, and a successful
solution to this problem will be described in a subsequent
report. Overall, starting from known aryl bromides 8 and
24, the syntheses of interiotherin A and angeloylgomisin R
were achieved in just seven steps.
tane 25 (Scheme 7). Bromination under mild conditions (27
h, CHCl3) occurred with complete regioselectivity to afford
the ortho-brominated product 20, identical with that previ-
ously prepared. This effectively transformed the cumbersome
three-step conversion of 17 f 18 f 19 f 20 (Scheme 5)
into the one-step transformation of 25 f 20 (Scheme 7).
The synthetic strategy developed for the asymmetric total
synthesis of interiotherin A and angeloylgomisin R provides
Acknowledgment. This work was supported by a grant
from the National Cancer Institute (R01 CA91904). We thank
Professor Tomislav Rovis for helpful discussions.
Supporting Information Available: Experimental pro-
cedures and spectral characterization of intermediates and
products. This material is available free of charge via the
Internet at http://pubs.acs.org.
(22) Magnus, P.; Sebhat, I. K. Tetrahedron 1998, 54, 15509.
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